Cyclopropyl-1,2,4-oxadiazolylpyridines

ABSTRACT

CYCLOPROPYL-1,2,4-OXADIAZOLYLPYRIDINES ARE DESCRIBED ALONG WITH METHODS OF PREPARING THE SAME. THESE COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF QUATERNARY CYCLOPROPYL - 1,2,4 - OXADIAZOLYLPYRIDINIUM SALTS, WHICH ARE ORAL HYPOLYCEMIC AGENTS. THESE COMPOUNDS ALSO SHOW DEPRESSANT PROPERTIES EVIDENCED BY THEIR ABILITY TO PREVENT CONVULSIVE SEIZURES IN ANIMALS CAUSED BY STRYCHNINE SULFATE.

United States Patent ice 3,555,036

Patented Jan. 12, 1971 3,555,036 the double bond is between the N and carbon containing CYCLOPROPYL-l,2,4-OXAD AZ L RIDINES the cyclopropyl substituent, and when Z has the other Victor John Bauer, Montvale, N.J.," William Joseph Fanshawe, Pearl River, NY. and Sidney Robert Salir River dg N assignors to American Cyanamid The compounds of the present invention may be pre Stamford n pared by TCEICUOH of cyclopropanecarboxyl c anhydrlde N. an...at;eirrzagstzazf.m... a pvndmecerbotamldqxlme, or a. 676,706, O t, 20, 1967 T i application No 10, 1969, propylcarboxamidoxirne with a pyridinecarboxylic acid Ser. No. 875,526 Y anhydride at elevated temperatures in the presence or ab- Int. Cl. C07d 31/42 sence of a solvent. US. Cl. 260-296 Claims 10 These reactions are illustrated schematically below:

meaning, the double bond is in the other position.

CH2 N on N 0 CH2 on, NOH u N 0 P011 ('1 o C I \N CH2 N on, NHZ 2 N Compounds within the scope of the present invention are, for example, ABSTRACT OF THE DISCLOSURE 2-(5-cyclopropyl)-1,2,4-oxadiazol-3-yl)pyridine,

Cyclopropyl-l,2,4-oxadiazolylpyridines are described 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridine, along with methods of preparing the same. These com- 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) pyridine, pounds are useful as intermediates in the preparation of 3-(3- Y P PY -y )Py quaternary cyclopropyl 1,2,4 oxadiazolylpyridinium 4-(5-cyclopropyl-l,2,4-oXadiazol-3-yl)pyridine, and salts, which are oral hypoglycemic agents. These com- 4-( y pr py DpY pounds also show depressant properties evidenced by their Th cyclopropyl-1,2,4-oxadiaz0lylpyridines of the presfl ll y to Pr convulsive SeiZllreS in animals s d ent invention are useful as intermediates in the synthesis y SUB/311111116 sulfate of quaternary cyclopropyl 1,2,4 oxadiazolylpyridinium compounds which are useful as oral hypoglycemic agents. Thus, a cyclopropyl 1,2,4 oxadiazolylpyridine is allowed to react with a lower alkyl halide to provide a 1- This application is a continuation-in-part of our application Ser. No. 676,706, filed Oct. 20, 1967, now abanlower (cyclopropyl 1,2,4 oxadiazolyD-pyridinium donedhalide. These reactions are illustrated by the formula:

PRIOR ART CH2 N Applicants are aware of British Pat. 875,887, directed /CH C to pyridinium salts. However, the present subject matter 2 Z N +10weralkylX is not disclosed nor is the utility described therein. E

SUMMARY OF THE INVENTION i This invention relates to new cyclopropyl-1,2,4-oxadi- Z N-10We1a1ky1X zolylpyridines which may be illustrated by the following wherein Z is d fi d as above d X i halogen formula:

. The compounds directly prepared from the interme- CHZ N diates of the present invention show hypoglycemic activ- I ity which indicates they are useful as medicaments. in the lowering of blood sugar levels. When the compounds are 0H2 Z administered orally to normal mice, a reduction of blood sugar levels is observed. Mice used in these studies are wherein Z is a trivalent radical selected from the group MF1 (Manor Farms, 18-25 grams). The compounds consisting of are administered by gavage as saline solutions. Control '1 'ltlmfh'lFd' H I H anima s receive an equiva en vo u e 0 ve ic e. o0 1s N-O and ON withheld from animals after dosing. Blood glucose is determined 3 hours after dosing by the method of Hoffman The dotted line represents one double bond, the position Biol Chem 120 51 (1937)] as adapted to the Tech Of which is dependent "P the definition of Z when nicon AutoAnalyzer and is expressed as percent change Z is V from saline controls. Blood samples are obtained from H the tail veins of mice. The testing data is summarized in Table I.

TABLE I.DECREASE BLOOD GLUCOSE IN NORMAL MICE AFTER ORAL ADMINISTRATION OF QUATERNARY CYCLOPROPYL-l,2,4-OXADIA- ZOLYL PYRIDINIUM SALTS Percent Dose, decrease mmoles/ in blood Compound kg. glucose 1-methy1-4-(5-cyclopropy1-1,2,4-oxadiazol3-y1)pyridiuium chloride 3. 0 87d: 3 1-methy1-4-(B-cyclopropyl-l,2,4-oxadiaz0l-3-y1)pyridinium chloride 3. 0 29:1: 4

In addition, the compounds of this invention show central nervous system depressant activity by protecting animals against convulsive seizures caused by strychnine. It has been reported [M. I. Gluckman, Pharmacology of oxazepam (Serax), a new antianxiety agent, Curr. Therap. Res, 1, 721 (1965)] that there is a high degree of correlation between anticonvulsant effects in animals and antianxiety effects in man. One measure of depressant activity is the ability to prevent convulsive seizures in warmblooded animals, e.g., mice, caused by strychnine sulfate [H. M. Hanson and C. A. Stone, Animal and Clinical Pharmacological Techniques in Drug Evaluation, vol. I, J. H. Nodine and P. E. Siegler, Eds., Yearbook Medical Publishers, Inc., Chicago, Ill., 1964, p. 317]. Graded dose levels of the compounds are administered intraperitoneally in a 2% aqueous starch medium to groups of ten mice at each dose. Strychnine sulfate, dissolved in aqueous saline is administered subcutaneously 30 minutes after drug treatment at doses estimated to cause toxic extensor seizures in 95 of the mice (0.82 milligram per kilogram of body weight). The median effective dose is calculated by the method of J. T. Litchfield and F. Wilcoxon [J. Pharmacol. Expt. Ther., 96, 99 (1949)]. The dose of 4-(5-cyclopropyl 1,2,4 oxadiazol-3-yl)pyridine which protects 50% of the mice from convulsive seizures caused by strychnine sulfate is 7 milligrams per kilogram intraperitoneally. Similarly effective are 30 milligrams per kilogram of 4-(3-cyclopropyl 1,2,4 oxadiazol-5-yl)pyridine, milligrams per kilogram of 3-(5- cyclopropyl 1,2,4 oxadiazol-3-yl)pyridine, and 7 milligrams per kilogram of 2-(5-cyclopropyl 1,2,4 oxadiazol-3-yl)pyridine. These data demonstrate that the compounds of the present invention are useful in warmblooded animals as muscle-relaxants and antianxiety agents.

DETAILED DESCRIPTION The examples which follow described the preparation of the novel compounds of the present invention.

EXAMPLE 1 Preparation of 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) pyridine A mixture of 5.4 g. of isonicotinamidoxime and 19 g. of cyclopropanecarboxylic acid anhydride is heated at 170 C. for 2 hours. The mixture is diluted with chloroform and washed with water and aqueous sodium carbonate. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a solid. Recrystallization from methanol-water gives tan crystals, melting point 7882 C.

EXAMPLE 2 Preparation of 4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl) pyridine A mixture of 4.6 g. of isonicotinic acid anhydride and 2.0 g. of cyclopropanecarboxamidoxime is heated at 170 C. for 90 minutes. The mixture is washed with aqueous sodium carbonate solution. The undissolved solid is collected and recrystallized from hexane to give creamcolored crystals, melting point 9293 C.

EXAMPLE 3 Preparation of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) pyridine A mixture of 27.4 g. of nicotinamidoxime, 30.8 g. of cyclopropanecarboxylic acid anhydride, and 200 ml. of xylene is heated under reflux for 2 hours and concentrated to a yellow liquid. The liquid is suspended in aqueous sodium carbonate, and the mixture is extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a liquid. Distillation gives a colorless liquid, boiling point 99-103 C. (0.25 111.111.).

4 EXAMPLE 4,

Preparation of 2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) pyridine A mixture of 27.4 g. of picolinamidoxime, 30.8 g. of cyclopropanecarboxylic acid anhydride, and 200 ml. of xylene is heated under reflux for 2 hours and concentrated to a yellow liquid. The liquid is suspended in aqueous sodium carbonate, and the mixture is extracted with chloroform. The chloroform solution is dried over anhydrous magnesium sulfate and concentrated to a liquid. Distillation gives a colorless liquid, boiling point 130-140 C. (0.20 mm.).

EXAMPLE 5 Preparation of 1-methyl-4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyridinium chloride A mixture of 3.0 g. of 4-(S-cyclopropyl-1,2,4-oxadiazol-3-yl)pyridine and 10 ml. of methyl chloride is heated in a bomb at C. for 20 hours. The excess methyl chloride is allowed to evaporate and the residue is recrystallized from acetonitrile to give off-white crystals, melting point 212-214 C.

EXAMPLE 6 Preparation of 1-methyl-4-(Pl-cyclopropyl-1,2,4-oxadiazol- 5-yl)pyridinium chloride A mixture of 4.0 g. of 4-(3-cyclopropyl 1,2,4 oxadiazol-5-yl)pyridine and 10 ml. of methyl chloride is heated in a bomb at 90 C. for 20 hours. The excess methyl chloride is evaporated and the residue is recrystallized from acetonitrile to give white crystals, melting point 221225 C.

We claim:

1. A cyclopropyl 1,2,4 oxadiazolylpyridine of the formula:

wherein Z is a trivalent radical selected from the group consisting of IUI(I) and )-1 I and the dotted line represents one double bond, the position being dependent upon the definition of Z.

2. The cyclopropyl 1,2,4 oxadiazolylpyridine accordto claim 1: 4-(5-cyelopropyl 1,2,4 oxadiazol-5-yl)pyridine.

3. The cyclopropyl 1,2,4 oxadiazolylpyridine according to claim 1: 4-(3-cyclopropyl 1,2,4 oxadiazol-S-yl) pyridine.

4. The cyclopropyl 1,2,4 oxadiazolylpyridine according to claim 1: 3-(5-cyclopropyl 1,2,4 oxadiazol-3-yl) pyridine.

5. The cyclopropyl 1,2,4 oxadiazolylpyridine according to claim 1: 2-(5-cyclopropyl 1,2,4 oxadiazol-B-yl) pyridine.

References Cited UNITED STATES PATENTS 2.733,245 1/ 1956 Ainsworth 260-296 FOREIGN PATENTS 875,887 8/1961 Great Britain 260296 ALAN L. ROTMAN, Primary Examiner U.S. C1. X.R. 260-295, 999 

